Stable topical drug delivery compositions

ABSTRACT

A method of delivering a drug composition comprises providing a carrier having a phosphatidylcholine component and a drug entrapped therein, and applying the composition to the skin for transdermal delivery of the drug, wherein the composition is stable at room temperature.

PRIOR APPLICATION

This application is a continuation of U.S. patent application Ser. No.10/749,914 filed Dec. 31, 2003, now pending, which claimed prioritybenefits under 35 U.S.C. §119(e) of U.S. Provisional Patent ApplicationSer. No. 60/437,279 filed Dec. 31, 2002. This application is also acontinuation of application Ser. No. 10/448,632 filed May 30, 2003, nowpending, which claimed priority benefits under 35 U.S.C. §119(e) of U.S.Provisional Patent Application No. 60/384,597, filed May 31, 2002.

FIELD OF THE INVENTION

The present invention relates to topical drug delivery compositions andmethods of transdermal drug delivery. More specifically, the presentinvention relates to stable drug delivery compositions for topicaladministration.

BACKGROUND OF THE INVENTION

Topical drug delivery systems are known. These systems deliver drugs,therapeutic agents and other desired substances transdermally and may bedesigned to act locally at the point of application or to actsystemically once entering the body's blood circulation. In thesesystems, delivery may be achieved by means such as direct topicalapplication of a substance or drug in the form of an ointment or thelike, or by adhesion of a patch with a reservoir or the like that holdsthe drug and releases it to the skin in a time-controlled fashion.

Transdermal delivery systems for agents such as drugs, pain relievingcompounds, vitamins, and skin improving compounds have been in use for anumber of years. These transdermal delivery systems using creams havebeen developed for use with analgesics and skin refining compounds.Transdermal systems using a patch have been developed for nicotine andestrogen therapies, for instance, estradiol technology described in U.S.Pat. No. 6,521,250 to Meconi, et al.

While effective for their purpose, these systems have typically onlybeen useful for transdermal delivery of relatively small molecules. Theskin's porous structure permits such small molecules to pass from theepidermis to the dermis via diffusion. However, large molecules, such asinsulin, are not able to diffuse through the skin and cannot bedelivered by these known means. One such solution has been provided inU.S. patent application Ser. No. 10/448,632 to Perricone, the disclosureof which is incorporated herein by reference.

While the delivery of large molecules such as insulin have beenaddressed, such systems do not address the storage and retention of theeffectiveness of the drug to be delivered. Many pharmaceuticals andbiologically active compounds, such as insulin, must be kept cool andaway from heat to remain effective and prevent denaturing at ambienttemperatures. Such substances may not be stored or carried (withoutrefrigeration) by the user. Often drugs like insulin must beadministered throughout the day and should be in ready-access to orcarried by the user, which may expose the compound to high temperatures.As such, there remains a need to stabilize compositions, includinginsulin, so that they are resistant to warmer temperatures and have alonger life at these temperatures without a need for refrigeration

SUMMARY OF THE INVENTION

A composition for transdermal delivery of a macromolecule comprises aphosphatidylcholine carrier component entrapping the macromolecule,wherein the carrier component stabilizes the macromolecule at roomtemperature.

A method for administering a drug or other active agent comprisesapplying to skin composition containing an effective amount of the drugor active agent, a carrier having a phosphatidylcholine componententrapping the drug or active agent.

DETAILED DESCRIPTION OF THE INVENTION

Phosphatidylcholine is used as a carrier for the topical delivery ofpolypeptides and macromolecules in the practice of this invention.Phosphatidylcholine is a basic component of cell membrane bilayers andthe main phospholipid circulating in the plasma. Phosphatidylcholine ishighly absorbable and supplies choline which is needed to facilitatemovement of fats and oils across and maintain cell membranes in animals.

Topical delivery compositions of the present invention are non-polar andformulated to contain polypeptides and macromolecules soluble inphosphatidylcholine, which are then applied to skin for transdermaldelivery of the macromolecule. Topical delivery compositions of theinvention are efficacious in the delivery of macromolecular drugs thatare conventionally administered intramuscularly, intravenously ororally, including, but not limited to polypeptides such as insulin andsomatropin, prostaglandins, glucocorticoids, estrogens, androgens, andthe like.

It is an advantage of the invention that topical administration of acomposition and transdermal delivery of the drug or active agent thereinis easier and pleasanter as an administration route than injections,particularly for drugs such as insulin that must be given to patientsover a period of time, or for a lifetime. Furthermore, unlike oraladministration where a substantial amount of the drug can be destroyedin the digestive process, the drugs in a topical application are notwasted. Topical application allows a steady diffusion of the drug to thedesired target area without the cyclic dosages typical of orally orparenterally administered drugs.

The term “phosphatidylcholine” as used herein means a mixture ofstearic, palmitic, and oleic acid diglycerides linked to the cholineester of phosphoric acid, commonly called lecithin. Many commerciallecithin products are available, such as, for example, those sold underthe tradenames Lecithol®, Vitellin®, Kelecin®, and Granulestin® becauselecithin is widely used in the food industry. Compositions of theinvention can contain synthetic or natural lecithin, or mixturesthereof. Natural preparations are preferred because they exhibitdesirable physical characteristics and are both economical and nontoxic.

Preferred topical delivery compositions of the present inventionadditionally contain polyenylphosphatidylcholine (herein abbreviated“PPC”) to enhance epidermal penetration. The term“polyenylphosphatidylcholine” as used herein means anyphosphatidylcholine bearing two fatty acid substituents, wherein atleast one is an unsaturated fatty acid with at least two double bondssuch as linoleic acid. Certain types of soybean lecithin and soybeanfractions, for example, contain higher levels ofpolyenylphosphatidylcholine, with dilinoleoyl-phosphatidylcholine(18:2-18:2 phosphatidylcholine) as the most abundant phosphatidylcholinespecies, than conventional food grade lecithin, and are useful informulating topical delivery compositions of the invention.Alternatively, conventional soybean lecithin is enriched withpolyenylphosphatidylcholine by adding soybean extracts containing highlevels of polyenylphosphatidylcholine. As used herein, this type ofphosphatidylcholine is called “polyenylphosphatidyl-choline-enriched”phosphatidylcholine (hereinafter referred to as PPC-enrichedphosphatidylcholine), even where the term encompasses lecithin obtainedfrom natural sources exhibiting polyenylphosphatidylcholine levelshigher than ordinary soybean varieties. These products are commerciallyavailable from American Lecithin Company, Rhône-Poulenc and otherlecithin vendors. American Lecithin Company markets its products with a“U” designation, indicating high levels of unsaturation; Rhône-Poulenc'sproduct is a soybean extract containing about 42%dilinoleoylphosphatidylcholine and about 24%palmitoyllinoleylphosphatidylcholine (16:0-18:2 PC) as the majorphosphatidylcholine components.

While not wishing to be bound to any theory, it is believed that thePPC-enriched phosphatidylcholine forms a bilayer enveloping thepolypeptide or macromolecule to create the topical drug deliverycomposition, contributing to the stability of the active molecule andenhancing penetration. Further, the topical drug delivery compositionmay be in liquid crystal phase, with the PPC-enrichedphosphatidylcholine loosely arranged in multilamellar fashion, with thepolypeptide or macromolecule being bonded and entrapped within the lipidbilayers formed therein, as disclosed in U.S. patent application Ser.No. 10/448,632 to Perricone. This forms a loosely arranged, yet stable,PPC-enriched phosphatidylcholine-drug complex that further increasespenetration and delivery of the polypeptide or macromolecule to thedermal vasculature.

Topical drug delivery compositions of the present invention provide anadministration route that is a marked improvement over conventionalinsulin injections, considerably easier and pleasanter. It is a furtheradvantage that compositions of the invention are also stable at roomtemperature, providing considerable convenience for insulin users who,in the past, have had to deal with the refrigerated insulin productscommercially available. Also, insulin compositions according to thepresent invention have longer shelf lives (whether stored at roomtemperature or refrigerated) and will not denature at room temperatureas would traditional insulin treatments.

Insulin useful in the topical drug delivery compositions of the presentinvention is commercially available from a variety of sources, marketedunder the tradenames Humulin®, Novolin®, Humalog®, Inutral®, amongothers. Some of these products contain porcine sequences. Compositionsof the invention are preferably formulated with recombinant humanpolypeptides such as those obtained from Sigma Co., Spectrum Chemicalsand Laboratories, and similar vendors and employed in the examples thatfollow. It is an advantage of the invention that topical drug deliverycompositions carrying insulin are formulated with commercially availableingredients.

Topical drug delivery compositions are generally formulated with acarrier comprising a PPC-enriched phosphatidylcholine material with thetrade name NAT 8729 (commercially available from vendors such asRhône-Poulenc and American Lecithin Company) and at least one polyglycol(polyhydric alcohol of a monomeric glycol such as polyethylene glycol(PEG) having molecular weights of 200, 300, 400, 600, 1000, 1450, 3350,4000, 6000, 8000 and 20000. Further, this carrier may comprise asurfactant such as a siloxylated polyether comprising dimethyl,methyl(propylpolyethylene oxide propylene oxide, acetate) siloxane orsilicone glycol copolymer fluid commercially available from vendors suchas Dow Corning, e.g. poly(oxyehtylene.oxypropylene) methyl polysiloxannecopolymer sold under the tradename Dow Corning 190 surfactant, andlubricant such as silicone fluids containing low viscositypolydimethylsiloxane polymers, methylparaben (p-hydroxy benzoic acidmethyl ester) commercially available from vendors such as Down Corning(under the tradename Dow Corning 200 silicone fluid). Additionally,purified water may be added to the carrier. The carrier is then mixedwith a preparation of the particular polypeptide(s) or macromolecule(s)in an amount to obtain the desired strength in the final composition.The following examples are presented to further illustrate and explainthe present invention and should not be taken as limiting in any regard.

EXAMPLE 1 Preparation of Stable Insulin Compositions

Stable insulin topical preparations were formulated by first preparing abase solution. A polyenylphosphatidylcholine material denoted NAT 8729which contained 80.6% PPC-enriched phosphatidylcholine and 4.9%lysophosphatidylcholine was obtained from Rhône-Poulenc. NAT 8729 (45%w/w) was shaved and added to a mixture of polyglycol E200 (50% w/w) andpolyglycol E400 (5% w/w) both obtained from Dow Corning. The basesolution was then covered well and lightning mixed with a specialdisintegration head impeller slowly at 800 rpm with slight heat. Thetemperature did not go above 40° C. Typical mixing times were 5 hours.The final solution is a crystal clear, viscous amber solution with nosediments or separations.

Into this base solution (97.25% w/w) was then mixed a Dow Corning Fluid190 (1.00% w/w) [a siloxylated polyether comprising dimethyl,methyl(propylpolyethylene oxide propylene oxide, acetate) siloxane]; aDow Corning silicone fluid denoted 200-5 or 10cst (1.00% w/w) [siliconefluids containing low viscosity polydimethylsiloxane polymers]; andmethylparaben [p-hydroxy benzoic acid methyl ester] obtained from vendorMallinckrodt (0.75% w/w). The ingredients were homogenized with 3850 rpmwith a 0.45 micron screen as follows. The methylparaben was first addedto the base solution and mixed for at least an hour until a completesolution formed. Then the Dow Corning 200-5 or 10 cst was slowly addedand mixed until a clear solution formed. Afterwards the Dow CorningFluid 190 was added slowly and mixed into the solution to form thecarrier.

Insulin preparations of the invention were then made using the carrierin two strengths: 50 units and 100 units, by simply dissolvingRNA-derived recombinant human insulin obtained from Sigma into thecarrier. It was readily soluble in the carrier.

In testing the stability of the stable insulin composition, insulinstandards were prepared at 1 mg/ml in 0.01 N HCl using Sigma insulin.(One mg of this material exhibits an activity of 28 insulin units.)Stable insulin compositions samples were prepared at 1 mg/1 ml base bymixing at room temperature for 60 minutes. This mixture was then dividedin half, half of which was stored at 4° C., and the other half stored atroom temperature. Separation analyses, High Performance LiquidChromatography (RP-HPLC) and High Performance Capillary Electrophoresis(HPCE), of insulin standards and insulin compositions of the inventionwhich were stored at different temperatures for different periods oftime were performed.

The RP-HPLC and HPCE analyses indicated that insulin standards that werestored at 4° C. or −20° C. were stable after 65 days, but insulinstandards stored at room temperature started to denature within 7 days.The RP-HPLC and HPCE profiles of insulin compositions of the invention,on the other hand, were stable at both room temperature and at 4° C.,and did not change after 65 days. The results clearly showed that thecarrier prevented the denaturing of the insulin stored at roomtemperature.

EXAMPLE 2 Preparation of Stable Insulin Compositions

Stable insulin compositions were formulated by first preparing a basesolution. Polyglycol E200 (PEG-200) (50% w/w) was weighed and polyglycolE400 (PEG-400) (5% w/w) was added to the same container to obtain thedesired weight, (both obtained from Dow Corning). PEG-200 and PEG-400were lightning mixed at 38-40° C. with IKA model RW20 using adisintegration head impeller slowly at 800 rpm (speed 1), yieldingPEG-200/PEG-400 solution. A PPC-enriched phosphatidylcholine materialdenoted NAT 8729 containing 80.6% PPC-enriched phosphatidylcholine and4.9% lysophosphatidylcholine was obtained from Rhône-Poulenc. NAT 8729(45% w/w) was shaved and added to PEG-200/PEG-400 solution, covered andmixed, with temperature not exceeding 40° C., until a clear, viscousamber solution with no sediments or separations resulted. The mixingtime was approximately five hours. An alternative mixture can beprepared by covering and mixing the solution overnight without heat fora 95-96% yield. The solution was removed from heat and transferred toRoss Homogenizer (Model HSM100LC) using smallest mesh screen.

A Dow Corning Fluid was then prepared. Dow Corning Fluid denominated 190(1.00% w/w) [a siloxylated polyether comprising dimethyl,methyl(propylpolyethylene oxide propylene oxide, acetate) siloxane] andDow Corning Fluid denoted 200-5 or 10 cst (1.00% w/w) [silicone fluidscontaining low viscosity polydimethylsiloxane polymers] were mixedtogether in a container with a clean spatula.

The solution (53.25% w/w) was warmed to 40° C. and mixed at 800 rpm.Typical mixing times were approximately 5 hours. The solution was thenmilled at 3800 rpm and the Dow Corning Fluid mixture was added veryslowly until a clear solution resulted. Methyl Paraben (p-hydroxybenzoic acid methyl ester) obtained from Mallinckrodt (0.75% w/w) wasadded at once and mixed until a complete solution resulted. Purifiedwater warmed to 40° C. was added very slowly to solution while millingat 7500 rpm for about three minutes. At end of milling, speed wasincreased to 10,000 rpm for few seconds before stopping. The solutionwas removed and swept with paddle head using IKA Model RW-20 untilcooled to room temperature. This step is very critical and if it is notdone properly it will generate a biphasic end product. The general ruleis to use a container having a volume twice that of the solution so thehomogenizer head is well embedded in the solution. The solution was thencooled to room temperature.

USP human recombinant insulin in obtained from Spectrum Chemicals andLaboratories (Product #11247) was prepared in 0.01 N HCl at 50 mg/ml,and gently, yet well mixed. This insulin preparation was then added veryslowly to the above solution to obtain a final concentration of 500units/ml or 20 mg/ml. Mixing was continued at room temperature for atleast one hour. The final stable insulin composition was stored at 4° C.in amber air-tight container.

RP-HPLC and HPCE analyses of insulin standards (prepared at 5 mg/ml in0.01 N HCl) and stable insulin compositions of the invention which werestored at different temperatures for different periods of time wereperformed. The results indicated that standard insulin standards storedat 4° were stable up to 22 weeks and started to denature after 34 weeks,whereas when stored at room temperature started to denature within only1 week. However, the stable insulin compositions prepared in accordancewith the above disclosures that were stored at room temperature werestable up to at least 22 weeks, which is 21 weeks longer than thestandard. The results showed no change in shelf-life from the standardfor stable insulin compositions stored at 4° C. (no change after 34weeks).

Stable topical drug delivery compositions of the present invention maybe employed to deliver and stabilize polypeptides transdermally,including but not limited to insulin, oxytocin, vasopressin, insulin,somatotropin, calcitonin, chorionic gonadotropin, menotropins,follitropins, somatostatins, progestins, and combinations of any ofthese. These drugs are readily available from a variety of commercialsources. Somatotropin (pituitary growth hormone) is marketed under thetradenames Gentropin®, Humatrope®, Nutropin®, and Serostim®.

A drug delivery composition formulated with somatotropin was formulatedin one trial with 85% phosphatidylcholine to which lipoic acid andascorbyl palmitate were added. Somatotropin readily dispersed inphosphatidyl-choline and remained stable in it. Growth hormone appearedto penetrate the skin well when the composition was topically applied.

The present invention may also be used to provide topical delivery ofactive agents other that drugs, for example, skin care agents. Theinvention is particularly useful with large molecules that are used insome cosmetic formulations, including peptides and polymers.

The above description is for the purpose of teaching the person ofordinary skill in the art how to practice the present invention, and itis not intended to detail all those obvious modifications and variationsof it which will become apparent to the skilled worker upon reading thedescription. It is intended, however, that all such obviousmodifications and variations be included within the scope of the presentinvention

1. A carrier composition for transdermal delivery of a macromolecule,comprising a polyenylphosphatidylcholine-enriched phosphatidylcholineand polyglycol mixture entrapping said macromolecule for transdermaldelivery to dermal vasculature, wherein said phosphatidylcholinecomponent stabilizes said macromolecule at room temperature.
 2. Thecomposition of claim 1, wherein said phosphatidylcholine and polyglycolmixture comprises two or more polyglycols.
 3. The composition of claim2, wherein at least one polyglycol is polyglycol having a molecularweight of 200 and another polyglycol is polyglycol having a molecularweight of
 400. 4. The composition of claim 3, wherein saidphosphatidylcholine and polyglycol mixture comprises 45% w/wpolyenylphosphatidylcholine-enriched phosphatidylcholine, 50% w/wpolyglycol having molecular weight of 200, and 5% w/w having molecularweight of
 400. 5. The composition of claim 1, further comprising asurfactant, a lubricant, and methyl paraben.
 6. The composition of claim5, comprising 97.25% w/w phosphatidylcholine and polyglycol mixture,1.00% w/w surfactant, 1.00% w/w lubricant, and 0.75% w/w methyl paraben.7. The composition of claim 5, further comprising water.
 8. Thecomposition of claim 7, comprising 53.25% w/w phosphatidylcholine andpolyglycol mixture, 1.00% w/w surfactant, 1.00% w/w lubricant, 0.75% w/wmethyl paraben and 44% w/w water.
 9. The composition of claim 5, whereinsaid surfactant is a siloxylated polyether.
 10. The composition of claim9, wherein said siloxylated polyether is dimethyl,methyl(propylpolyethylene oxide propylene oxide, acetate) siloxane. 11.The composition of claim 5, wherein said lubricant is silicone fluid.12. The composition of claim 11, wherein said silicone fluid containslow viscosity polydimethylsiloxane polymers.
 13. The composition ofclaim 1, wherein said macromolecule is selected from the groupconsisting of oxytocin, vasopressin, insulin, somatotropin, calcitonin,chorionic gonadotropin, menotropins, follitropins, somatostatins,progestins, peptides, polymers, and combinations of any of these. 14.The composition of claim 1, wherein said macromolecule comprises insulinentrapped within said carrier for transdermal delivery of the insulin todermal vasculature.